Hemodialysis is an important clinical procedure for the removal of toxic biological metabolites in patients with end-stage renal disease. The central element of a hemodialysis instrument is the semipermeable membrane which allows for selective transport of low molecular weight biological metabolites, in particular urea and creatinine, from blood. The semipermeable membranes used in hemodialysis instruments may be made from natural or synthetic polymeric materials. Cellulose is used almost exclusively to make the natural hemodialysis membranes. Synthetic membranes are typically made from hydrophobic e.g., (poly(methyl methacrylate) and polycarbonate! and hydrophilic (e.g., polyacrylonitrile and polysulfone) polymers. Currently, most clinically used hemodialysis instruments are equipped with cellulosic membranes.
Surface-induced thrombosis and serum complement activation are two of the most serious consequences of blood-cellulose membrane interactions in hemodialysis. Thrombosis is initiated by the adsorption of plasma proteins, followed by the adhesion and activation of platelets. When activated, platelets secrete adenosine diphosphate (ADP), serotonin, and other granular contents to activate other resting platelets and the coagulation cascade reaction. Platelet activation results in mural thrombus formation on hemodialysis membranes, potentially embolizing into the blood stream. Currently, surface-induced thrombosis is minimized by heparin infusion during the hemodialysis procedure. Large doses of heparin needed for anticoagulation can lead to uncontrolled bleeding episodes that can be fatal.
The complement system acts as a first line defense mechanism against microbial infections and the presence of foreign materials in the body. The complement system, consisting of 30 different proteins, can be activated by the classical pathway or the alternative pathway. Cellulose-based membranes are known to activate the alternative pathway of the complement system due to covalent interaction between the C3b fragment of complement and the surface-accessible hydroxyl groups of cellulose. Complement activation leads to a transient decrease in white blood cell count observed during 30 m of treatment. Release of cytokines and other biological mediators by complement activation may also lead to downstream complications such as hemodialysis intolerance, pulmonary hypertension, and immune suppression.
Since the interactions leading to thrombosis and complement activation occur at the blood-membrane interface, attempts have been made to modify cellulose membrane surfaces by covalent grafting of poly(ethylene glycol), C.sub.16 -C.sub.18 alkyl chains to selectively adsorb albumin from plasma, and heparin to improve blood compatibility. Surface modification of cellulose membranes by covalent grafting assures that the modifying agent will not be removed or displaced during blood contact. Unfortunately, the methods of covalent grafting are cumbersome and, in some cases, require the use of toxic organic solvents. Furthermore, the covalently-modified cellulose membranes could have lower permeability profiles than the unmodified membranes.
Cationic polymers such as chitosan have been proposed for the development of membranes and fibers for hemodialysis and blood oxygenators, skin substitute and wound dressing material, as a matrix for immobilization of enzymes and cells, for binding with bile and fatty acids, and as a vehicle for drug and gene delivery. Chitosan, a linear polymer of D-glucosamine, is obtained by alkaline N-deacetylation of chitin. Chitosan has excellent film forming properties and high mechanical strength which make it suitable for hemodialysis membranes. Unfortunately, however, chitosan promotes plasma protein adsorption, platelet adhesion and activation, and thrombus development.
Therefore, it would be desirable to employ cationic polymers such as chitosan in making biocompatible articles such as membranes and fibers for hemodialysis and blood oxygenators, skin substitute and wound dressing material, etc., which have the advantages of the base material, but avoid the use of covalent surface modification techniques, but offer long-term blood compatibility of covalently-modified membranes.